Of the 35 million living with HIV in the world today, small percentages have never received therapy but retain adequate CD4 help and resist progression to AIDS. To date, the immunological constraints leading to this so-called long-term non-progression (LTNP) state remain largely unknown. Certain non-neutralizing antibodies (Abs) have shown protection and control in HIV challenge model systems and the non-neutralizing antibody-dependent cell-cytotoxicity function is thought to play a role in protection seen in the recent RV144 vaccine `Thai Trial'.We have previously isolated a number of non-neutralizing Abs from LTNP subjects' B cells that target two non-linear conformational trimer-dependent epitopes in the HIV surface envelope protein gp41. In preliminary studies these epitopes are present on advanced vaccine candidates that replicate the native surface HIV envelope trimer. In preliminary serum competition studies, targeting of these gp41 non-linear conformational trimer dependent epitopes is more prevalent in LTNP subjects; with 50- 75% of LTNP subjects having high Ab titers. We hypothesize that Abs targeting these non-linear conformational trimer dependent epitopes assist in maintaining the LTNP state by functional targeting of native surface envelope structure. To explore rates of epitope targeting in LTNP subjects, we will recruit a larger number (45 minimum in each arm) of LTNP to compare levels to progressing subjects, maintained on therapy, and HIV negative control samples. We have established collaborations at HIV care clinics across New York State. To measure binding of these structurally targeted Abs to a panel of HIV antigens including proposed vaccine constructs, we will recombinantly express a panel of HIV antigens containing gp41 epitopes. This panel will include leading vaccine candidates and mutated forms of antigen to confirm specificity of binding. ELISA based assays, native gel shift assays and surface plasmon resonance will be used to confirm binding and characterize the specificity of targeted antigen. To identify the function of these Abs in assisting the LTNP state, we will test antibody dependent cell cytotoxicity by these Abs. By fully characterizing the non-linear conformational trimer dependent Abs and their targets, we will provide the basis for future immunogenicity studies to test if these epitopes can assist in protection or control.